Methods for the preparation of 1,3-benzodioxole heterocyclic compounds

ABSTRACT

The present invention relates to novel methods for the preparation of 1,3-benzodioxole heterocyclic compounds and intermediates for the same. The compounds are useful as PDE4 inhibitors.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/062,760 filed Jun. 15, 2018, which is a national stage filing under35 U.S.C. § 371 of International Application No. PCT/EP2016/081368 filedDec. 16, 2016, which claims priority to European Patent Application No.15201053.4 filed Dec. 18, 2015. The contents of these applications areeach incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to novel methods for the preparation of1,3-benzodioxole heterocyclic compounds and intermediates for the same.The compounds are useful as PDE4 inhibitors.

BACKGROUND OF THE INVENTION

WO 2011/160632 discloses benzodioxole and benzodioxepene heterocycliccompounds useful as PDE4 inhibitors as well as suitable methods for thepreparation thereof.

WO 2008/104175 discloses benzodioxole and benzodioxepene heterocycliccompounds useful as PDE4 inhibitors as well as suitable methods for thepreparation thereof.

WO 2008/077404 discloses substituted acetophenones useful as PDE4inhibitors as well as suitable methods for the preparation thereof.

PCT/EP2015/063942, earliest priority date of 23 Jun. 2014, disclosesmethods for the preparation of 1,3-benzodioxole heterocyclic compounds.

Zafrani et al. Tetrahedron 65, 2009, pp 5278-5283, describes a methodfor the difluoromethylation of phenols and thiophenols.

Sperry et al Org. Process Res. Dev. 15, 2011, pp 721-725, also describesthe difluoromethylation of phenols.

Frey et al. Tetrahedron 2003, 59, pp. 6363-6373 also describes thedemethylation and difluoromethylation of phenols

Zhang et al. J. Org. Chem. 2006, 71, 9845-9848 also describes thedifluoromethylation of phenols.

Zheng et al. Chem. Commun. 2007, 5149-5151 also describes thedifluoromethylation of phenols.

In the development of new drug candidates, it is highly desirable tohave access to alternative methods for the preparation of the drugcandidates, as some efficient small-scale synthesis may turn out to bedifficult to up-scale to production scale quantities. Also, small-scalesyntheses may involve reagents and solvents which are not feasible toutilize at a production scale level.

Hence, it is an object of the present invention to provide alternativemethods for the preparation of 1,3-benzodioxole heterocyclic compoundsof the type disclosed in WO 2011/160632 and PCT/EP2015/063942, insofarthat such alternative methods provide advantages with respect to one ormore features like the number of reactions steps, purity, yield, ease ofpurification, process economy, availability of starting materials andreagents, safety, predictability, etc.

Surprisingly, in step (2a) of the present invention, the yield is ≥80%,which by far surpasses the yield of 32% obtained in the deprotection ofthe phenol group in the method as described in WO 2011/160632. Further,the method as described in WO 2011/160632 relies on chromatography forthe purification of the product, whereas the present method makes itpossible to purify the product by simple unit operations easily scalablein a production plant.

Further, surprisingly, in step (3) of the present invention, thedifluoromethyl group can now be introduced in a yield of 76% with orwithout isolating an intermediate salt. This surpasses the yield of 52%as obtained by the method as in described in WO 2011/160632. Further,the method as described in WO 2011/160632 relies on chromatography forthe purification of the product, whereas the present method makes itpossible to purify the product by very simple unit operations easilyscalable in a production plant.

The improved yield and the easy scale up of the process of the presentinvention as compared to the method as described in WO 2011/160632, arequite surprising.

SUMMARY OF THE INVENTION

It has been found by the present inventors that the alternative methoddisclosed herein provides advantages over the known methods by a reducednumber of steps, an improved overall chemical and volumetric yield andan accompanying reduced cost for the production.

Hence, the present invention provides a method for the preparation of1,3-benzodioxole compounds, e.g., a compound of formula (I).

Also within the scope of the invention are intermediates used in theforegoing method for preparing compounds of formula (I).

DETAILED DISCLOSURE OF THE INVENTION

In a first aspect, the present invention relates to a method for thepreparation of a compound of formula (I)

wherein R₁ is selected from CHF₂ and CF₃, and Q is selected from chloro,bromo and fluoro.

In the compound of formula (I), R₁ is typically CHF₂. Q is typicallyselected from chloro, bromo and fluoro, preferably chloro, where the Q'spreferably are the same. In one embodiment, both Q's are chloro.

Definitions

The term “C₁₋₆-alkyl” is intended to mean a saturated, straight orbranched hydrocarbon chain having from one to six carbon atoms,including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondarybutyl, tertiary butyl, pentyl, isopentyl, neopentyl, tertiary pentyl,hexyl and isohexyl. In some embodiments, “C₁₋₆-alkyl” is a C₁₋₄-alkylgroup, e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,secondary butyl and tertiary butyl. Correspondingly, “C₁₋₃-alkyl”includes methyl, ethyl, propyl and isopropyl.

The term “halogen” is intended to mean one of fluoro, chloro, bromo andiodo. In one embodiment, the term “halogen” designates fluoro or chloro.In another embodiment, the term “halogen” designates chloro.

The term “aryl” is intended to mean a carbocyclic aromatic ring systemderived from an aromatic hydrocarbon by removal of a hydrogen atom. Arylfurthermore includes bi-, tri- and polycyclic ring systems. Examples ofpreferred aryl moieties include phenyl, naphthyl, indenyl, indanyl,fluorenyl, and biphenyl. Preferred “aryl” is phenyl, naphthyl orindanyl, in particular phenyl, unless otherwise stated.

The term “arylalkyl” is intended to mean an aryl radical as definedabove covalently joined to an alkyl group, e.g., benzyl.

Methods of Preparation

It appears that the method provides advantages over the known methods byrelying on cheap starting materials, ease of the production method, andincreasing yields in the reactions.

Step (1)

The method for the preparation of a compound of the formula (I) includesthe formation of a compound of the formula (IV) which is obtained byreacting a compound of formula (II)

wherein R₂ is selected from hydrogen, C₁₋₆-alkyl and arylalkyl, R₂₁ isselected from hydrogen and C(O)R₂₂, and R₂₂ is selected from hydrogenand C₁₋₆-alkyl; with a compound of formula (III)

wherein “

” represents a single bond, a double bond or two single bonds, and when“

” represents a double bond or two single bonds, “

” is a single bond, and when “

” represents a single bond, “

” is a double bond; R₃ represents oxygen when “

” represents a double bond and R₃ represents O—C₁₋₆-alkyl when “

” represents a single bond or two single bonds; in the presence of anacid catalyst to form a compound of formula (IV)

wherein R₂ and R₂₁ is as defined above.

The acid catalyst is typically in form of a silicate mineral. Thesilicate mineral is typically selected from Montmorillonite K10,Montmorillonite K30, Montmorillonite KSF, Zeolite HSZ-341NHA, ZeoliteHSZ-331NHA, Zeolite HSZ-350HUA and Zeolite HSZ-360HUA. In oneembodiment, the silicate mineral is selected from Montmorillonite K10and Zeolite HSZ-360HUA. In another embodiment, the silicate mineral isMontmorillonite K10.

The compound of formula (III) is typically selected from

wherein R₃₁ represents C₁₋₆-alkyl. In one embodiment, the compound offormula (III) is selected from the compounds of formula (IIIa), andformula (IIIb), wherein R₃₁ represents methyl. In another embodiment,the compound of formula (III) is tetrahydrothiopyran-4-one.

The ratio between the silicate mineral and compound of formula (II) mayhave influence on the conversion and filtration-time. Hence, it istypically preferred to have an amount of the mineral of 25%-w/w to500%-w/w compared to the compound of formula (II). In particular theamount of mineral should be of 25%-w/w to 75%-w/w. preferably in therange 45%-w/w to 55%-w/w.

The reaction is typically conducted in toluene, benzene, 2-Methyl-THF(2-methyl-tetrahydrofuran), EtOAc (ethyl acetate), xylenes, heptane,octane, chlorbenzene and dichlorbenzene. In one embodiment, the solventis toluene.

The reaction is typically conducted at a temperature above 80° C. inorder to promote the reaction. Hence, it is typically preferred that thetemperature is in the range of 80-200° C., such as in the range of100-160° C., especially at 105-115° C. In one embodiment, the reactionis performed at reflux of the reaction mixture. The reaction istypically allowed to proceed for 4-96 hours, such 24-84 hours,especially 48-84 hours.

The resulting compound of formula (IV) may be recovered by conventionalmeans, known to those skilled in the art, e.g., by aqueous workupfollowed by extraction and finally precipitation and filtration.

In one embodiment of the invention, the compound of formula (II) iswherein R₂ is selected from hydrogen or methyl and R₂₁ is selected fromhydrogen, COCH₃ or COOH.

In another embodiment, the compound of formula (II) is1-(2,3-dihydroxy-4-methoxyphenyl)ethanone.

In one embodiment of the invention, the compound of formula (III) istetrahydrothiopyran-4-one.

In one embodiment of the invention, the compound of formula (IV) iswherein R₂ is hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl,secondary butyl, tertiary butyl or benzyl, and R₂₁ is selected fromhydrogen, COCH₃ or COOH. In another embodiment the compound of formula(IV) is wherein R₂ is methyl and R₂₁ is COCH₃.

Step (2a)

The compound of the formula (IV)

wherein R₂ and R₂₁ is as defined above, is converted to a compound offormula (VI)

wherein R₂₁ is defined above by deprotecting the phenol moiety.

This may be done by reacting the compound of formula (IV) with anaromatic or aliphatic thiol in combination with a base.

The aromatic thiol may be e.g., but is not limited to, benzenethiol,4-methylbenzene-thiol, 3,5-dimethylbenzenethiol,2,5-dimethylbenzenethiol, 4-isopropylbenzenethiol, or5-tert-butyl-2-methyl-benzenethiol. In one embodiment, the aromaticthiol is 5-tert-butyl-2-methyl-benzenethiol.

The aliphatic thiol may be e.g., but is not limited to, 1-dodecanethiol,1-tetra-decanethiol, 1-hexadecanethiol, or tert-dodecanethiol. In oneembodiment, the aliphatic thiol is 1-dodecanethiol.

The deprotection of the phenol group in step (2a) may be conducted usingvarious solvents, e.g. selected from DMF (N,N-dimethylformamide), NMP(N-methylpyrrolidone), DMSO (dimethyl sulfoxide), methanol, or ethanoland mixtures hereof.

In one embodiment, the solvent is DMF. In another embodiment, thesolvent is a mixture of DMF and methanol.

The deprotection of the phenol group is performed in the presence of abase, e.g. selected from K₂CO₃, Na₂CO₃, KHCO₃, NaHCO₃, CsCO₃, TEA(triethylamine), potassium tert-butoxide, tert-BuOLi (lithiumtert-butoxide), sodium methoxide, sodium ethoxide, and DIPEA(N,N-diisopropylethylamine). In one embodiment, the base is K₂CO₃. Inanother embodiment, the base is sodium methoxide.

The reaction is typically conducted at a temperature in the range of50-120° C., such as in the range of 70-100° C. The reaction is typicallyallowed to proceed for 2-36 hours, such as 3-24 hours. The reaction istypically allowed to proceed until the conversion is ≥98%.

The resulting compound of formula (VI) may be recovered by conventionalmeans, known to those skilled in the art, e.g. by aqueous workupfollowed by extraction and finally precipitation and filtration.

In one embodiment of the invention, the compound of formula (VI) iswherein R₂₁ is C(O)R₂₂, and R₂₂ is selected from hydrogen andC₁₋₆-alkyl. In another embodiment the compound of formula (VI) is1-(7-hydroxyspiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl)ethanone.

Step (2b)

In step (2b) the compound of formula (VI) is reacted with aqueous N(Bu)₄⁺OH⁻ to form a compound of formula (VII)

wherein R₂₁ is as defined above.

The mixture is typically heated to a temperature in the range of 20-80°C., such as 55-65° C., until all has dissolved.

The resulting solution is typically washed with a solution of sodiumchloride in water by stirring at a temperature in the range of 20-80°C., such as 55-65° C. for ≥20 min. Subsequently adding a mixture ofwater and sodium chloride followed by cooling of the mixture from ≥35°C. to 0-20° C., e.g., 5° C. over a period of 1-24 hours, such as 1-4hours, causes the TBA (tetrabutylammonium) salt to precipitate. The TBAsalt is isolated e.g., by filtration and dried.

Step (3)

The compound of formula (IX)

wherein R₁ and R₂₁ are as defined above, may be obtained by alkylatingthe resulting compound of formula (VII)

wherein R₂₁ is as defined above, by reacting with ahydrochlorofluorocarbon reagent,

R₁—Cl  (VIII)

wherein R₁ is as defined above.

The alkylation may be conducted using one of various possible reagents,such as various hydrochlorofluorocarbon gases. In one embodiment, thealkylation reaction is conducted using chlorodifluoromethane in anaprotic polar solvent, e.g. selected from DMF (N,N-dimethylformamide),NMP (N-methylpyrolidone), DMI (1,3-dimethyl-2-imidazolidinone), DMSO(dimethyl sulfoxide), EtOAc (ethyl acetate), MeCN (acetonitrile) and THF(tetrahydrofuran), and mixtures hereof. In one preferred embodiment, theaprotic solvent is selected from DMF and NMP. In a particularembodiment, the reaction is conducted using chlorodifluoromethane inDMF.

The reaction is typically conducted at a temperature in the range of40-120° C., such as in the range of 50-70° C. The reaction is typicallyallowed to proceed until 54% of the phenol is left in the reactionmixture.

The resulting compound of formula (IX) may be recovered by conventionalmeans, known to those skilled in the art, e.g., by aqueous workupfollowed by precipitation and subsequently filtration.

In one embodiment of the invention, the compound of the formula (IX) is1-[7-(difluoromethoxy)spiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl]ethanone.

Alternative Step (2b+3)

Alternatively, the compound of formula (IX),

wherein R₁ and R₂₁ are as defined above, may be obtained from thecompound of formula (VI),

wherein R₂₁ is defined above, without forming the intermediate salt ofthe formula (VII), by using a difluorocarbene source in a polar solventin the presence of a base.

The difluorocarbene source is selected from e.g., but not limited to,sodium chlorodifluoroacetate, diethyl bromodifluoromethylphosphonate,chlorodifluoromethyl phenyl sulfone, and2-chloro-2,2-difluoroacetophenone. Those skilled in the art can easilychoose other suitable analogous of the mentioned difluorocarbenesources. In one embodiment, the difluorocarbene source is sodiumchlorodifluoroacetate. In another embodiment, the difluorocarbene sourceis diethyl bromodifluoromethylphosphonate.

The reaction is performed in a solvent selected from e.g., NMP(N-methylpyrolidone), DMI (1,3-dimethyl-2-imidazolidinone), DMSO(dimethyl sulfoxide), EtOAc (ethyl acetate), MeCN (acetonitrile), THF(tetrahydrofuran), ethanol, methanol, water, and mixtures hereof. In oneembodiment, the solvent is a mixture of water and DMF. In anotherembodiment, the solvent is a mixture of water and acetonitrile.

The reaction is performed in the presence of a base selected from e.g.K₂CO₃, Na₂CO₃, KHCO₃, NaHCO₃, CsCO₃, TEA (triethylamine), tert-BuOLi(lithium tert-butoxide), sodium methoxide, sodium ethoxide, DIPEA(N,N-diisopropylethylamine), KOH, NaOH, LiOH. In one embodiment, thebase is K₂CO₃. In another embodiment, the base is NaOH.

The reaction is typically conducted at a temperature in the range of0-120° C., such as 6-115° C. In one embodiment, the reaction isperformed at 6-20° C. using diethyl bromodifluoromethylphosphonate asdifluorocarbene source. In another embodiment, the reaction is performedat ambient temperature to 111° C. using sodium chlorodifluoroacetate asdifluorocarbene source.

In one embodiment of the invention, the compound of the formula (IX) is1-[7-(difluoromethoxy)spiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl]ethanone.

The resulting compound of formula (IX), wherein R₁ and R₂₁ are asdefined above, may be recovered by conventional means, known to thoseskilled in the art, e.g. by aqueous workup followed by precipitation andsubsequently filtration.

Step (4)

In step (4), the compound of formula (IX) is reacted with a pyridinecompound of formula (X)

wherein Q is as defined above and Q_(x) is selected from chloro, bromo,fluoro and iodo to form a compound of formula (XI)

wherein R₁ and Q are as defined above.

The pyridine coupling in step (4), is typically conducted in an polarsolvent, e.g. selected from DMF (N,N-dimethylformamide), NMP(N-methylpyrrolidone), DMI (1,3-dimethyl-2-imidazolidinone), DMSO(dimethyl sulfoxide), MeCN (acetonitrile) and THF (tetrahydrofuran), andmixtures hereof, in the presence of a base, e.g. selected from tert-BuOK(potassium tert-butoxide), tert-BuOLi (lithium tert-butoxide),tert-BuONa (sodium tert-butoxide), sodium or potassium methoxide, sodiumor potassium ethoxide, K₂CO₃, Na₂CO₃, KHCO₃, NaHCO₃, Et₃N(triethylamine) and DIPEA (N,N-diisopropylethylamine). In oneembodiment, the solvent is DMF and the base is tert-BuOK.

Usually two equivalents or more of the base is used relative to thecompound of the formula (IX), such as where the molar ratio(base)/(formula IX) is from 5:1 to 2:1, e.g. from 3:1 to 2:1, especiallyfrom 2.4:1 to 2.7:1.

The reaction in step (4) is typically conducted at a temperature of0-40° C., such as 5-25° C.

In one embodiment of the invention, the compound of formula (X) is3,4,5-trichloropyridine.

In one embodiment of the invention, the compound of formula (XI) is2-(3,5-dichloro-4-pyridyl)-1-[7-(difluoromethoxy)spiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl]ethanone.

During the reaction, an impurity of formula (XII) is formed inconsiderable amounts.

This impurity is purged from the product by crystallising the productfrom a solvent selected from e.g., dimethylformamide (DMF), ethanol,methanol, ethyl acetate, hexane, heptane, and mixtures thereof. In oneembodiment of the invention, the solvent is a mixture of ethyl acetateand ethanol.

Step (5)

The oxidation of the resulting compound of formula (XI) is conducted toform the compound of formula (I)

wherein R₁ and Q are as defined above, by reacting said compound offormula (XI) with an oxidation reagent.

The oxidation reagent is typically selected from PAA (peracetic acid) inAcOH (acetic acid), and H₂O₂ (aq) in formic acid or acetic acid. In onepreferred embodiment, the oxidation reagent is PAA in AcOH. In oneembodiment the amount of PAA used relative to (XI) (molar ratio) istypically 3 to 6, such as 3.8 to 4.2. The oxidation reagent is typicallyslowly added over a period of 1-8 hours, such as 3-5 hours, keeping thetemperature in the range of 15-100° C., such as in the range of 15-50°C., especially in the range of 15-40° C.

The reaction is typically conducted at a temperature in the range of30-70° C., such as 40-60° C., especially 48-52° C., and stirred for 3-48hours, such as 16-24 hours.

Purification of the Compound of Formula (I)

The resulting crude product of formula (I) may advantageously bepurified by crystallization, precipitation, chromatography or the like.

In one embodiment the resulting crude product of formula (I) iscrystallized from a mixture of water and EtOH (ethanol), and isolated byfiltration and dried.

The Intermediates

In another aspect, the present invention relates to intermediates whichare useful in the preparations of a compound of the formula (I) whereinR₁ is selected from CHF₂ and CF₃, and Q is selected from chloro, bromoand fluoro.

In one embodiment the invention relates to the intermediate compound offormula (VI)

wherein R₂₁ is selected from hydrogen and C(O)R₂₂, and R₂₂ is selectedfrom hydrogen and C₁₋₆-alkyl. In another embodiment, the intermediatecompound of formula (VI) is1-(7-hydroxyspiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl)ethanone.

In another embodiment the invention relates to the intermediate compoundof formula (VII)

wherein R₂₁ is selected from hydrogen and C(O)R₂₂, and R₂₂ is selectedfrom hydrogen and C₁₋₆-alkyl. In another embodiment, the intermediatecompound of formula (VII) is tetrabutylammonium7-acetylspiro[1,3-benzodioxole-2,4′-tetrahydro-thiopyran]-4-olate.

In another embodiment the invention relates to the intermediate compoundof formula (IX)

wherein R₁ is selected from CHF₂ and CF₃, and R₂₁ is selected fromhydrogen and C(O)R₂₂, and R₂₂ is selected from hydrogen and C₁₋₆-alkyl.

In another embodiment R₁ represents CHF₂, and R₂₁ is C(O)R₂₂ and R₂₂ isselected from hydrogen and C₁₋₆-alkyl. In another embodiment, theintermediate compound of formula (IX) is1-[7-(difluoromethoxy)spiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl]ethanone.

EXPERIMENTALS

Methods and Reagents

All chemicals and reagents used were available from commercial sources.

¹H nuclear magnetic resonance (NMR) spectra were recorded at theindicated magnetic field and chemical shift values (δ, in ppm) arequoted in the specified solvent relative to tetramethylsilane (δ=0.00).

HPLC: Column: Aeris Peptide 3.6 μm XB-C18, 100×4.6 mm, the eluent was agradient of A: 10% MeCN; 90% H2O; 0.1% TFA and B: 90% MeCN; 10% H2O;0.1% TFA, column temperature: 35° C., UV detection at 220 nm, flow rate:1.5 mL/min. The following gradients of the eluents were used:

Gradient steps 2a, 2b, 3, and 5 Time (min) % A % B 0 85 15 8 20 80 10 2080 10 85 15 12.2 85 15

Gradient Step 4 Time (min) % A % B 0 75 25 5 20 80 12.2 20 80 12.2 75 2513.2 75 25

Example 1 Step (1): Preparation of1-(7-methoxyspiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl)ethanone

A reactor was charged with 1-(2,3-dihydroxy-4-methoxy-phenyl)ethanone(60.0 kg, 329 mol), tetrahydrothiopyran-4-one (37.2 kg, 320 mol),Montmorillonite K 10 (30.0 kg), and toluene (720.0 L). The mixture wasstirred with heating to reflux, applying a jacket temperature of140-150° C. for 84 hours. The mixture was cooled to 86-90° C. andfiltered through a bed of filter aid. The reactor was rinsed with hot(86-90° C.) toluene (120 L), and the hot toluene was then used to washthe bed of filter aid. The rinse of the reactor and the following washof the bed of filter aid was repeated two times with hot toluene (120L), and once with hot (70° C.) ethyl acetate (60 L). All the toluene andethyl acetate filtrates were combined and cooled to 2-6° C. overapproximately 6 hours. The mixture was stirred at 2-6° C. forapproximately half an hour.

Unconverted starting material was collected by filtration, and dried invacuo at 43-47° C. Yield 32.0 kg.

The filtrate from the isolation of unconverted starting material wascooled to 10-16° C. with stirring, and a mixture of sodium hydroxide(26.40 kg) and water (162.0 L) was added at 10-16° C. The reactionmixture was then stirred for approximately half an hour at 10-16° C.,then the agitation was stopped, and the phases were allowed to settle.The lower aqueous phase was discarded, and then a mixture of sodiumhydroxide (26.40 kg) and water (162 L) was added with stirring at 10-16°C. The mixture was stirred for approximately one hour, then agitationwas stopped, and the phases were allowed to settle. The lower aqueousphase was discarded and the organic phase was transferred to acontainer. The reactor was rinsed with toluene, and then the organicphase was transferred back to the reactor through a Cartridge filter.

The solution was concentrated as much as possible in vacuo applying atemperature of 570° C. Ethanol (90.0 L) was added, and the mixture washeated to 47-53° C., and stirred at that temperature for 10-15 minutes.Then the mixture was concentrated as much as possible in vacuo at atemperature ≤55° C. Ethanol (120.0 L) was added to the reactor, themixture was heated to reflux with stirring, and water (90.0 L) was addedwith heating, keeping the mixture at reflux. The mixture was cooled to2-8° C. over approximately 10 hours and stirred at that temperature forapproximately half an hour.

The product was isolated by filtration, washed with a mixture of ethanol(30.0 L) and water (22.8 L), and dried in vacuo at 43-47° C. Yield 21.80kg (24% but 51% if corrected for recovered starting material). 1H NMR(600 MHz, DMSO-d6) δ 7.30 (d, J=9.0 Hz, 1H), 6.75 (d, J=9.0 Hz, 1H),3.88 (s, 3H), 2.91-2.84 (m, 2H), 2.84-2.77 (m, 2H), 2.49 (s, 3H),2.30-2.22 (m, 2H), 2.22-2.12 (m, 2H).

Step (1) was repeated as necessary in order to produce the needed amountof1-(7-methoxyspiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl)ethanone.

Step (2a): Preparation of1-(7-hydroxyspiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl)ethanone

A reactor was charged with1-(7-methoxyspiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl)ethanone(26.0 kg, 92.7 mol), potassium carbonate (14 kg, 101 mol),dimethylformamide (104 L), and 5-tert-butyl-2-methyl-benzenethiol (26.8kg, 149 mol). The mixture was heated with stirring to 85-92° C. until aconversion of ≥98% was achieved, as indicated by HPLC. The mixture wasthen cooled to 25° C., added water (104 L) and sodium hydroxide (28% inwater, 21.4 kg), and stirred for ≥10 minutes. If pH of the mixture wasbelow 12, more sodium hydroxide (28% in water) was added. Then toluene(65 L) was added, and stirring was continued for ≥15 minutes. Theagitation was stopped, and the phases were allowed to settle. The phaseswere separated and the organic phase was discarded. The two loweraqueous phases were stirred with toluene (65 L) and the mixture wasstirred for ≥15 minutes. The agitation was stopped, allowing the phasesto settle. The phases were separated and the organic phase wasdiscarded. The two aqueous phases were returned to the reactor andhydrochloric acid (18% in water, 67.6 kg) was added slowly with stirringin order to control the gas evolution. The resulting mixture was stirredfor ≥10 minutes. More hydrochloric acid (18% in water, 10.2 kg) wasadded in order to achieve pH 56.

The temperature of the mixture was adjusted to 35-45° C. and kept thereduring the following extractions. Ethyl acetate (156 L) was added andthe mixture was stirred for 30 minutes. The stirring was stopped, andthe phases were allowed to settle. The phases were separated. Theaqueous phase was stirred with ethyl acetate (78 L) for 30 minutes. Theagitation was stopped, and the phases were allowed to settle. Theaqueous phases was discarded. The two ethyl acetate phases were combinedin the reactor and stirred with water (78 L) for ≥15 minutes. Thestirring was stopped, and the phases were allowed to separate. Theaqueous phase was discarded.

The organic phases were concentrated as much as possible with a jackettemperature of 50-60° C. and applying a vacuum. Then heptane (39 L) wasadded, and the resulting mixture was cooled to 55° C. with a rate of510° C./h, and kept at that temperature for 3 hours. The title compoundwas isolated by filtration, washed with a cold (55° C.) mixture of ethylacetate (10 L) and heptane (10 L), and dried in vacuo at 40-50° C. Yield19.75 kg (80%). 1H NMR (600 MHz, DMSO-d6) δ 10.51 (s, 1H), 7.18 (d,J=9.0 Hz, 1H), 6.50 (d, J=9.0 Hz, 1H), 2.93-2.85 (m, 2H), 2.84-2.78 (m,2H), 2.46 (s, 3H), 2.31-2.23 (m, 2H), 2.20-2.11 (m, 2H).

Step (2b): Tetrabutylammonium7-acetylspiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-olate

1-(7-hydroxyspiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl)ethanone(19.75 kg, 74.16 mol) was charged to a suitable reactor followed bytetrabutylammonium hydroxide (40% solution in water, 53.0 kg, 81.7 mol).The jacket temperature was set to 60° C. and the mixture was stirreduntil all had dissolved. A saturated solution of sodium chloride inwater (59.2 kg) was added and stirring was continued with a jackettemperature of 60° C. for ≥20 minutes. The agitation was stopped,allowing the phases to separate. The lower aqueous phase was discarded.The mixture in the reactor was stirred again with a jacket temperatureof 60° C. A saturated solution of sodium chloride in water (29.6 kg) andthen water (25 L) were added. The mixture was stirred for 15 minutes ata temperature ≥35° C. in the mixture. The mixture was cooled to 0-5° C.at a rate of approximately 20° C./hr, the mixture was seeded at 40° C.and again at 35° C. The mixture was stirred at 0-5° C. for ≥2 hours, andthen the title compound was isolated by filtration and dried in vacuo at40-50° C. Yield 32.9 kg (87%). 1H NMR (600 MHz, DMSO-d6) δ 6.94 (d,J=9.1 Hz, 1H), 5.74 (d, J=9.1 Hz, 1H), 3.23-3.07 (m, 8H), 2.87-2.72 (m,4H), 2.25 (s, 3H), 2.16-2.07 (m, 2H), 2.06-1.96 (m, 2H), 1.62-1.51 (m,8H), 1.30 (h, J=7.4 Hz, 8H), 0.93 (t, J=7.4 Hz, 12H).

Step (3):1-[7-(difluoromethoxy)spiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl]ethanone

Tetrabutylammonium7-acetylspiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-olate (32.93kg, 64.85 mol) and dimethylformamide (198 L) were added to a reactor.The mixture was stirred until all had dissolved. Chlorodifluoromethane(39.5 kg, 457 mol) was added to the solution via a dip pipe on thereactor. The reaction mixture was heated to 50-55° C. and stirred until54% of the starting material was left as indicated by HPLC. The reactionmixture was cooled to 20-25° C. and transferred to a container via afilter. The reactor and the solid in the filter was washed withdimethylformamide (10 L) which was added to the container as well.

Water (198 L) and sodium hydroxide (28% in water, 11.0 kg) were chargedto the reactor and heated to 45-55° C. The reaction mixture in thecontainer was added slowly to the reactor with stirring, keeping thetemperature at 45-55° C. The mixture was then cooled to 5-10° C. andstirred at that temperature for 2 hours. The product was isolated byfiltration, washed with water (82 L), and dried in vacuo at 45-55° C.with a bleed of nitrogen. Yield 19.08 kg (94%). 1H NMR (600 MHz,DMSO-d6) δ 7.34 (t, J=73.1 Hz, 1H), 7.32 (d, J=9.1 Hz, 1H), 6.86 (d,J=9.1 Hz, 1H), 2.92-2.80 (m, 4H), 2.54 (s, 3H), 2.34-2.27 (m, 2H),2.27-2.19 (m, 2H).

Step (4)2-(3,5-dichloro-4-pyridyl)-1-[7-(difluoromethoxy)spiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl]ethanone

Dimethyl formamide (96 L) was charged to a suitable reactor followed byaddition of potassium tert-butoxide (17.60 kg, 156.8 mol). Transfer ofpotassium tert-butoxide was ensured with a rinse of dimethyl formamide(3 L), and the mixture was stirred until potassium tert-butoxide haddissolved. The solution was transferred from the reactor to a container,the reactor was rinsed with dimethyl formamide (6 L), which wastransferred to the container as well.

The reactor was charged with1-[7-(difluoromethoxy)spiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl]ethanone(19.08 kg, 60.32 mol), 3,4,5-trichloropyridine (14.30 kg, 78.38 mol),and dimethylformamide (96 L). The mixture was stirred and cooled to10-15° C., and then the solution of potassium tert-butoxide indimethylformamide was added slowly, keeping the temperature of thereaction mixture at 5-25° C. The transfer of the potassium tert-butoxidesolution was ensured with a rinse of dimethyl formamide (6 L). Themixture was heated to 20-25° C. and stirred until the conversion was≥98% as indicated by HPLC. Content of the impurity of formula (XII) inthe reaction mixture: 12%

Water (96 L) was added slowly with cooling to the reaction mixturekeeping the temperature between 20-30° C. This was followed by theaddition of saturated sodium chloride in water (115.2 kg) and ethylacetate (134 L). The mixture was stirred for 20-60 minutes and then theagitation was stopped, allowing the phases to settle. The phases wereseparated, and the aqueous phase was returned to the reactor. Ethylacetate (96 L) was added, and the mixture was stirred for 20-60 minutes.The agitation was stopped, allowing the phases to settle. The phaseswere separated. The organic phases were combined in the reactor andstirred with water (48 L) and saturated sodium chloride in water (57.8kg) for ≥20 minutes. The agitation was stopped allowing the phases tosettle. The lower aqueous phase was discarded, and water (48 L) andsaturated sodium chloride (57.6 kg) were added. The mixture was agitatedfor 20-60 minutes, and then the agitation was stopped, allowing thephases to settle. The lower aqueous phase was discarded, and water (84L) and sodium hydroxide (28% in water, 14.0 kg) were added. The mixturewas stirred for 20-60 minutes and then the agitation was stopped,allowing the phases to settle. The lower aqueous phase was discarded.

The organic phase in the reactor was concentrated by use of vacuum andheating with a jacket temperature of 50-65° C. to a residual volume ofapproximately 40 L. Ethanol (57 L) was charged to the reactor, and themixture was heated to reflux until a clear solution was obtained. Themixture was cooled to 5° C. over ≥5 hours and stirred at thattemperature for 3 hours. The product was isolated by filtration,transfer was ensured with a rinse of ethanol (10 L). The product waswashed with cold (≤5°) ethanol (48 L) and dried in vacuo at 45-55° C.Yield 15.57 kg (56%). 1H NMR (600 MHz, Chloroform-d) δ 8.52 (s, 2H),7.46 (d, J=8.9 Hz, 1H), 6.80 (d, J=8.9 Hz, 1H), 6.73 (t, J=73.3 Hz, 1H),4.59 (s, 2H), 3.01-2.85 (m, 4H), 2.47-2.30 (m, 4H). HPLC: Purity: 97.8%,content of the impurity of the formula (XII): 1.0%.

Step (5):2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[7-(difluoromethoxy)-1′,1′-dioxo-spiro[1,3-benzodioxole-2,4′-thiane]-4-yl]ethanone

A reactor was charged with2-(3,5-dichloro-4-pyridyl)-1-[7-(difluoromethoxy)-spiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl]ethanone(15.6 kg, 33.7 mol) and glacial acetic acid (78.0 kg) and the mixturewas cooled to 13-20° C. Per acetic acid (36-40% in acetic acid, 6.52 kg,32.6 mol) was added slowly keeping the temperature below 40° C. Themixture was heated to 40-50° C. and stirred for 10-25 minutes. Themixture was cooled to 13-20° C. and a second portion of per acetic acid(36-40% in acetic acid, 6.51 kg, 32.5 mol) was added slowly keeping thetemperature below 40° C. The mixture was heated to 40-50° C. and stirredfor 10-25 minutes. The mixture was cooled to 20-30° C. and a thirdportion of per acetic acid (36-40% in acetic acid, 14.3 kg, 71.5 mol)was added slowly. The mixture was heated to 48-55° C. and stirred untilthe conversion was ≥98.5%. The mixture was cooled to 20-25° C. and amixture of sodium metabisulphite (7.21 kg, 37.9 mol) and water (46 L)was added slowly keeping the temperature below 35° C.

2-propanol (78 L) was added and the mixture was heated to 60-65° C. andfiltered hot. The reactor was cleaned and the filtrated reaction mixturewas returned to the reactor. The mixture was heated to 60-65° C. andwater (234 L) was added slowly keeping the temperature above 55° C. Themixture was stirred for 30-60 minutes at 60-65° C., cooled slowly to 5°C. over 12 hours, and stirred at 0-10° C. for 2 hours. The raw productwas isolated by filtration, washed with water (27 L), and dried in vacuofor approximately two hours.

The solid was returned to the reactor and heated to reflux with ethanol(390 L). The mixture was then cooled to 68-72° C. and seeded. Themixture was cooled to 5° C. over 13 hours and stirred at 0-10° C. for 2hours. The product was isolated by filtration, washed with a cold (0-10°C.) mixture of water (4 L) and ethanol (39 l), and dried in vacuo at45-55° C. with a bleed of nitrogen. Yield 14.6 kg (85%). 1H NMR (600MHz, Chloroform-d) δ 8.23 (s, 2H), 7.52 (d, J=9.1 Hz, 1H), 6.90 (d,J=9.1 Hz, 1H), 6.71 (t, J=72.3 Hz, 1H), 4.49 (s, 2H), 3.47-3.38 (m, 2H),3.33-3.24 (m, 2H), 2.83-2.75 (m, 2H), 2.75-2.68 (m 2H). HPLC: purity98.6%.

Example 21-(7-hydroxyspiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl)ethanone

Sodium methoxide in methanol (30%, 64.2 mL, 0.34 mol) was added to asolution of1-(7-methoxyspiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl)ethanone(50.0 g, 0.178 mol) in dimethylformamide (250 mL) at 25-30° C. Then1-dodecane-thiol (64.88 mL, 0.271 mol) was added at 25-30° C. and themixture was heated to 95-100° C. for three hours. The reaction mixturewas cooled to 25-30° C. and sodium hydroxide (28% in water, 50 mL) andwater (250 mL) were added. The resulting mixture was stirred for half anhour and then the mixture was extracted with toluene (250 mL) threetimes. The aqueous solution was acidified with hydrochloric acid (6M) toapproximately pH 6 and extracted with ethyl acetate (250 mL) four times.The ethyl acetate extracts were combined, washed with brine (250 mL)four times, and concentrated to approximately 50 mL using a rotaryevaporator. Heptane (300 mL) was added and the mixture was stirred forone hour at ambient temperature. The product was isolated by filtration,washed with heptane (100 mL), and dried. Yield 44.3 g (93%). NMRcomplied with NMR of the product from step (2a) in Example 1.

Example 31-[7-(difluoromethoxy)spiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl]-ethanone

A mixture of1-(7-hydroxyspiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl)ethanone(221.6 g, 0.8322 mol), potassium carbonate (161.3 g, 1.167 mol), sodiumchlorodifluoroacetate (292.0 g, 1.915 mol), dimethylformamide (1.50 L),and water (500 mL) was stirred in a 5 liter reaction flask and heatedslowly to 106-111° C., gas evolution was observed from approximately 78°C. The reaction mixture was stirred at 106-111° C. until the gasevolution had ceased, approximately two hours. The mixture was cooledwith an ice-water bath, and water (1.00 L) was added slowly at 30-32° C.The resulting suspension was cooled further to 6° C. under stirring. Theraw product was isolated by filtration and washed with water.

The wet raw product was stirred with ethyl acetate (1.66 L) and sodiumhydroxide (1 M, 560 mL) for approximately 20 minutes, and then thephases was separated in a separatory funnel. The lower aqueous phase wasdiscarded and the organic phase was washed twice with water (two times560 mL). The organic phase was concentrated using a rotary evaporator(in vacuo with 60° C. in the water bath) to approximately 450 mL. Ethylacetate (1.56 L) was added, and the mixture was concentrated again usinga rotary evaporator as above to approximately 450 mL. Ethyl acetate(1.44 L) was added, and the unclear solution was filtered, transferringand washing with a fresh portion of ethyl acetate (100 mL). The combinedfiltrates were filtered through a plug of activated carbon (6.0 g),transferring and washing with ethyl acetate (200 mL). The combinedfiltrates were concentrated on a rotary evaporator as above toapproximately 450 mL. The resulting hot solution (approximately 60° C.)was stirred at ambient temperature while heptane (2.00 L) was addedslowly over approximately half an hour. The suspension was stirred atambient temperature for 14 hours.

The mixture was stirred in an ice-water bath for approximately 2.5hours, the temperature of the mixture was then 4° C. The product wasisolated by filtration, washed with an ice-cold mixture of heptane andethyl acetate (10:1, 200 mL), and dried in vacuo at 50° C. with a bleedof air. Yield 201 g (76%). NMR complied with NMR of the product fromstep 3 in example 1.

Example 41-[7-(difluoromethoxy)spiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl]-ethanone

Sodium hydroxide (6.16 g, 154 mmol) was dissolved in water (40 mL) andthe solution was stirred with cooling in an ice-water bath.1-(7-hydroxyspiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl)ethanone(2.00 g, 7.51 mmol) and acetonitril (20 mL) were added, and stirringwith cooling was continued. Diethyl bromodifluoromethylphosphonate (2.67mL, 15.0 mmol) was added in one portion at 6° C., and stirring withcooling was continued for approximately 20 minutes. The cooling bath wasremoved, and the mixture was stirred for approximately 21 hours atambient temperature.

The phases were separated using a separatory funnel, and the water phasewas extracted with ethyl acetate (20 mL). The combined organic phaseswere washed with water (20 mL) and then with brine (20 mL). The organicphase was concentrated to dryness using a rotary evaporator as inexample 3. Ethyl acetate (20 mL) was added to the residue, and themixture was concentrated to dryness once again using the rotaryevaporator.

The residue was dissolved in ethyl acetate (30 mL) and filtered,transferring and washing with ethyl acetate (20 mL). The combinedfiltrates were concentrated to dryness using a rotary evaporator asabove, giving the title compound as a yellowish solid. Yield 2.14 g(90%). NMR complied with NMR of the product from step 3 in example 1.

Example 51-[7-(difluoromethoxy)spiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl]-ethanone

Sodium hydroxide (301 g, 7.52 mol) was stirred with water (2.0 L), andthe resulting solution was cooled with an ice-water bath.1-(7-hydroxyspiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl)ethanone(100.1 g, 0.3757 mol) and acetonitrile (1.0 L) were added. Diethylbromodifluorophosphonate (150.5 g, 0.5637 mol) was added slowly overapproximately 40 minutes at a temperature of 15-20° C. in the reactionmixture. Stirring was continued for another approximately two hours at15-20° C. The phases were separated.

Water (920 mL) was added slowly to the organic phase with stirring andthe resulting suspension was stirred at ambient temperature forapproximately 18 hours. The product was isolated by filtration, washedwith a 1:1 mixture of acetonitrile and water (120 mL), and dried invacuo at 50° C. with a bleed of air. Yield 108 g (91%). NMR compliedwith NMR of the product from step 3 in example 1.

Clauses

In view of the description the present inventors have in particularprovided:

Clause 0. A method for the preparation of a compound of formula (I)

wherein R₁ is selected from CHF₂ and CF₃, Q is selected from chloro,bromo and fluoro, comprising one or more of the following steps:

(1) reacting a compound of formula (II)

wherein R₂ is selected from hydrogen, C₁₋₆-alkyl and arylalkyl, R₂₁ isselected from hydrogen and C(O)R₂₂, and R₂₂ is selected from hydrogenand C₁₋₆-alkyl; with a compound of formula (III)

wherein “

” represents a single bond, a double bond or two single bonds, and when“

” represents a double bond or two single bonds, “

” is a single bond, and when “

” represents a single bond, “

” is a double bond; R₃ represents oxygen when “

” represents a double bona and R₃ represents O—C₁₋₆-alkyl when “

” represents a single bond or two single bonds; in the presence of anacid catalyst to form a compound of formula (IV)

wherein R₂ and R₂₁ is as defined above;

(2a) reacting the resulting compound of formula (IV) with an aromatic oraliphatic thiol, to form a compound of formula (VI)

wherein R₂₁ is defined above;

(2b) reacting the compound of formula (VI) with aqueous N(Bu)₄ ⁺OH⁻ toform a compound of formula (VII)

wherein R₂₁ is as defined above;

(3) alkylating the resulting compound of formula (VII) with ahydrochlorofluorocarbon reagent,

R₁—Cl  (VIII)

wherein R₁ is as defined above, to form a compound of formula (IX)

wherein R₁ and R₂₁ are as defined above;

(4) reacting the compound of formula (IX) with a pyridine compound offormula (X)

wherein Q is as defined above and Q_(x) is selected from chloro, bromo,fluoro and iodo to form a compound of formula (XI);

wherein R₁ and Q are as defined above; and

(5) oxidating the resulting compound of formula (XI) to prepare thecompound of formula (I)

wherein R₁ and Q are as defined above.

Clause 1. A method for the preparation of a compound of formula (I)

wherein R₁ is selected from CHF₂ and CF₃, Q is selected from chloro,bromo and fluoro, comprising each of the following steps:

(1) reacting a compound of formula (II)

wherein R₂ is selected from hydrogen, C₁₋₆-alkyl and arylalkyl, R₂₁ isselected from hydrogen and C(O)R₂₂, and R₂₂ is selected from hydrogenand C₁₋₆-alkyl; with a compound of formula (III)

wherein “

” represents a single bond, a double bond or two single bonds, and when“

” represents a double bond or two single bonds, “

” is a single bond, and when “

” represents a single bond, “

” is a double bond; R₃ represents oxygen when “

” represents a double bond and R₃ represents O—C₁₋₆-alkyl when “

” represents a single bond or two single bonds; in the presence of anacid

catalyst to form a compound of formula (IV)

wherein R₂ and R₂₁ is as defined above;

(2a) reacting the resulting compound of formula (IV) with an aromatic oraliphatic thiol, to form a compound of formula (VI)

wherein R₂₁ is defined above;

(2b) reacting the compound of formula (VI) with aqueous N(Bu)₄ ⁺OH⁻ toform a compound of formula (VII)

wherein R₂₁ is as defined above;

(3) alkylating the resulting compound of formula (VII) with ahydrochlorofluorocarbon reagent,

R₁—Cl  (VIII)

wherein R₁ is as defined above, to form a compound of formula (IX)

wherein R₁ and R₂₁ are as defined above;

(4) reacting the compound of formula (IX) with a pyridine compound offormula (X)

wherein Q is as defined above and Q_(x) is selected from chloro, bromo,fluoro and iodo to form a compound of formula (XI);

wherein R₁ and Q are as defined above; and

(5) oxidating the resulting compound of formula (XI) to prepare thecompound of formula (I)

wherein R₁ and Q are as defined above.

Clause 2. The method according to clause 1 wherein the deprotection instep (2a) is conducted in a solvent e.g., selected from NMP, DMSO, DMF,methanol, ethanol and mixtures hereof, in the presence of a base, e.g.,selected from K₂CO₃, Na₂CO₃, KHCO₃, NaHCO₃, CsCO₃, TEA and DIPEA,potassium tert-butoxide, lithium tert-butoxide, sodium methoxide, sodiumethoxide.

Clause 3. The method according to clause 2 wherein the solvent is DMFand the base is K₂CO₃.

Clause 4. The method according to clause 2 where the solvent is amixture of DMF and methanol and the base is sodium methoxide.

Clause 5. The method according to any one of the preceding clauseswherein the reaction in step (3) is conducted using ahydrochlorofluorocarbon R₁—Cl compound in the presence of a polarsolvent, e.g., selected from DMF, NMP, DMI, DMSO, EtOAc and THF.

Clause 6. The method according to clause 5 wherein the reaction isconducted using chlorodifluoromethane in DMF.

Clause 7. The method according to any one of the preceding clauseswherein in step (4) the coupling is conducted in a polar solvent, e.g.,selected from NMP, DMF, DMI, DMSO, MeCN and THF, and mixtures hereof, inthe presence of a base, e.g. selected from tert-BuOK, tert-BuOLi,tert-BuONa, sodium or potassium methoxide, sodium or potassium ethoxide,K₂CO₃, Na₂CO₃, KHCO₃, NaHCO₃, Et₃N and DIPEA.

Clause 8. The method according to clause 7 wherein the polar solvent isDMF, and the base is tert-BuOK.

Clause 9. The method according to any one of the preceding clauseswherein R₁ is CHF₂.

Clause 10. The method according to any one of the preceding clauseswherein all of Q and Q_(x) are chloro.

Clause 11. The method according to any one of the preceding clauseswherein the impurity of formula (XII)

is purged from the product obtained in step (4) by crystallising saidproduct from a solvent selected from e.g., dimethylformamide (DMF),ethanol, methanol, ethyl acetate, hexane, heptane, and mixtures thereof.

Clause 12. The method according to clause 11, wherein the solvent is amixture of ethyl acetate and ethanol.

Clause 13. An intermediate compound of formula (VI)

wherein R₂₁ is selected from hydrogen and C(O)R₂₂, and R₂₂ is selectedfrom hydrogen and C₁₋₆-alkyl.

Clause 14. The intermediate compound according to clause 13 which is1-(7-hydroxyspiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl)ethanone.

Clause 15. An intermediate compound of formula (VII)

wherein R₂₁ is selected from hydrogen and C(O)R₂₂, and R₂₂ is selectedfrom hydrogen and C₁₋₆-alkyl.

Clause 16. The intermediate compound according to clause 15 which istetrabutylammonium7-acetylspiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-olate.

Clause 17. An intermediate compound of formula (IX)

wherein R₁ is selected from CHF₂ and CF₃, and R₂₁ is selected fromhydrogen and C(O)R₂₂, and R₂₂ is selected from hydrogen and C₁₋₆-alkyl.

Clause 18. The intermediate compound according to clause 17 which is1-[7-(difluoromethoxy)spiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl]ethanone.

Clause 19. A method for preparing a compound of formula (VI)

wherein R₂₁ is selected from hydrogen and C(O)R₂₂, and R₂₂ is selectedfrom hydrogen and C₁₋₆-alkyl, comprising reacting the compound offormula (IV) with an aliphatic or aromatic thiol.

Clause 20. The method according to clause 19, wherein the thiol is1-dodecane-thiol.

Clause 21. The method according to clause 19, wherein the thiol is5-tert-butyl-2-methyl-benzenethiol Clause 22. A method for preparing acompound of formula (VII)

wherein R₂₁ is selected from hydrogen and C(O)R₂₂ and R₂₂ is selectedfrom hydrogen and C₁₋₆-alkyl, comprising step (1), (2a) and (2b) asdefined in clause 1.

Clause 23. A method for preparing a compound of formula (VII)

wherein R₂₁ is selected from hydrogen and C(O)R₂₂ and R₂₂ is selectedfrom hydrogen and C₁₋₆-alkyl, comprising step (2a) and (2b) as definedin clause 1.

Clause 24. A method for preparing a compound of formula (VII)

wherein R₂₁ is selected from hydrogen and C(O)R₂₂, and R₂₂ is selectedfrom hydrogen and C₁₋₆-alkyl, comprising step (2b) as defined in clause1.

Clause 25. A method for preparing a compound of formula (IX)

wherein R₁ is selected from CHF₂ and CF₃, and R₂₁ is selected fromhydrogen and C(O)R₂₂, and R₂₂ is selected from hydrogen and C₁₋₆-alkyl;comprising step (2b) and (3) as defined in clause 1.

Clause 26. A method for preparing a compound of formula (IX)

wherein R₁ is selected from CHF₂ and CF₃, and R₂₁ is selected hydrogenand C(O)R₂₂, and R₂₂ is selected from hydrogen and C₁₋₆-alkyl;comprising step (3) as defined in clause 1.

Clause 27. A method for preparing a compound of formula (IX)

wherein R₁ is selected from CHF₂ and CF₃, and R₂₁ is selected fromhydrogen and C(O)R₂₂, and R₂₂ is selected from hydrogen and C₁₋₆-alkyl;comprising reacting the compound of formula (VI) with a difluorocarbenesource in a polar solvent in the presence of a base.

Clause 28. The method according to clause 27, wherein thedifluorocarbene source is sodium chlorodifluoroacetate.

Clause 29. The method according to clause 27, wherein thedifluorocarbene source is diethyl bromodifluoromethylphosphonate.

Clause 30. The method according to clause 28, wherein the polar solventis a mixture of water and DMF.

Clause 31. The method according to clause 29, wherein the polar solventis a mixture of water and acetonitrile.

Clause 32. The method according to clause 30, wherein the base is K₂CO₃.

Clause 33. The method according to clause 31, wherein the base is NaOH.

Clause 34. A method for preparing a compound of formula (I)

wherein R₁ is selected from CHF₂ and CF₃, and Q is selected from chloro,bromo and fluoro, obtained by method of clause 1.

Clause 35. A method for preparing a compound of formula (I)

wherein R₁ is selected from CHF₂ and CF₃, and Q is selected from chloro,bromo and fluoro, comprising each of the steps (2a), (2b), (3) and (4)as defined in clause 1, and subsequently oxidation of the resultingcompound.

Clause 36. A method for preparing a compound of formula (I)

wherein R₁ is selected from CHF₂ and CF₃, and Q is selected from chloro,bromo and fluoro, comprising each of the steps (2b), (3) and (4) asdefined in clause 1, and subsequently oxidation of the resultingcompound.

Clause 37. A method for preparing a compound of formula (I)

wherein R₁ is selected from CHF₂ and CF₃, and Q is selected from chloro,bromo and fluoro, comprising each of the steps (3) and (4) as defined inclause 1, and subsequently oxidation of the resulting compound.

Clause 38. A method for preparing a compound of formula (I)

wherein R₁ is selected from CHF₂ and CF₃, and Q is selected from chloro,bromo and fluoro, comprising each of the steps: (2a), (2b+3) and (4),and subsequently oxidation of the resulting compound.

Clause 39. A compound of formula (I)

wherein R₁ is selected from CHF₂ and CF₃, and Q is selected from chloro,bromo and fluoro, obtained by method of clause 1.

Clause 40. A compound of formula (I)

wherein R₁ is selected from CHF₂ and CF₃, and Q is selected from chloro,bromo and fluoro, made by the steps (2a), (2b), (3) and (4) as definedin clause 1, followed by oxidation of the resulting compound.

Clause 41. A compound of formula (I)

wherein R₁ is selected from CHF₂ and CF₃, and Q is selected from chloro,bromo and fluoro, made by the steps (2b), (3) and (4) as defined inclause 1, followed by oxidation of the resulting compound.

Clause 42. A compound of formula (I)

wherein R₁ is selected from CHF₂ and CF₃, and Q is selected from chloro,bromo and fluoro, made by the steps (3) and (4) as defined in clause 1,followed by oxidation of the resulting compound.

Clause 43. A compound of formula (I)

wherein R₁ is selected from CHF₂ and CF₃, and Q is selected from chloro,bromo and fluoro, made by the steps (2a), (2b+3) and (4), followed byoxidation of the resulting compound.

1.-15. (canceled)
 16. A method for the preparation of a compound offormula (I)

wherein R₁ is selected from CHF₂ and CF₃, Q is selected from chloro,bromo and fluoro, comprising the following steps: (2b+3) reacting thecompound of formula (VI),

with a difluorocarbene source reagent in a polar solvent in the presenceof a base to obtain the compound of formula (IX),

wherein R₂₁ is C(O)CH₃, and wherein R₁ is as defined above; (4) reactingthe compound of formula (IX) with a pyridine compound of formula (X)

wherein Q is as defined above and Q_(x) is selected from chloro, bromo,fluoro, and iodo, to form a compound of formula (XI);

wherein R₁ and Q are as defined above; and (5) oxidizing the resultingcompound of formula (XI) to obtain the compound of formula (I).
 17. Themethod according to claim 16, wherein the difluorocarbene source isselected from sodium chlorodifluoroacetate, diethylbromodifluoromethylphosphonate, chlorodifluoromethyl phenyl sulfone, and2-chloro-2,2-difluoroacetophenone.
 18. The method according to claim 17,wherein the difluorocarbene source is sodium chlorodifluoroacetate. 19.The method according to claim 16, wherein the reaction in step (2b+3) isperformed in a solvent selected from NMP (N-methylpyrolidone), DMI(1,3-dimethyl-2-imidazolidinone), DMSO (dimethyl sulfoxide), EtOAc(ethyl acetate), MeCN (acetonitrile), THF (tetrahydrofuran), ethanol,methanol, and water, or mixtures thereof.
 20. The method according toclaim 16, wherein the reaction in step (2b+3) is performed in a mixtureof water and DMF (N,N-dimethylformamide).
 21. The method according toclaim 16, wherein the base in the reaction in step (2b+3), is selectedfrom K₂CO₃, Na₂CO₃, KHCO₃, NaHCO₃, CsCO₃, TEA (triethylamine),tert-BuOLi (lithium tert-butoxide), sodium methoxide, sodium ethoxide,DIPEA (N,N-diisopropylethylamine), KOH, NaOH, and LiOH.
 22. The methodaccording to claim 21, wherein the base is K₂CO₃.
 23. The methodaccording to claim 16, wherein the reaction in step (2b+3) is performedin the temperature range of 6-115° C.
 24. The method according to claim16, wherein, in the reaction in step (2b+3) the difluoromethylatingreagent is sodium chlorodifluoroacetate, the polar solvent is a mixtureof N,N-dimethylformamide and water, and the base is K₂CO₃.
 25. Themethod according to claim 16, wherein the reaction in step (4) isconducted in a polar solvent selected from DMF (N,N-dimethylformamide),NMP (N-methylpyrrolidone), DMI (1,3-dimethyl-2-imidazolidinone), DMSO(dimethyl sulfoxide), MeCN (acetonitrile), and THF (tetrahydrofuran), ormixtures thereof, in the presence of a base selected from tert-BuOK(potassium tert-butoxide), tert-BuOLi (lithium tert-butoxide),tert-BuONa (sodium tert-butoxide), sodium or potassium methoxide, sodiumor potassium ethoxide, K₂CO₃, Na₂CO₃, KHCO₃, NaHCO₃, Et₃N(triethylamine) and DIPEA (N,N-diisopropylethylamine).
 26. The methodaccording to claim 25, wherein the reaction in step (4) is conducted inDMF and the base is tert-BuOK.
 27. The method according to claim 25,wherein the molar ratio of the base to the compound of formula (IX) isfrom 5:1 to 2:1.
 28. The method according to claim 16, wherein thereaction in step (4) is conducted at a temperature of 0-40° C.
 29. Themethod according to claim 16, wherein, in the reaction in step (4), thecompound of formula (XI) is crystalised from a solvent selected fromdimethylformamide (DMF), ethanol, methanol, ethyl acetate, hexane, andheptane, or a mixture thereof.
 30. The method according to claim 29,wherein the solvent is a mixture of ethyl acetate and ethanol.
 31. Themethod according to claim 16, wherein, in the reaction in step (5) theoxidizing agent is selected from PAA (peracetic acid) in AcOH (aceticacid), H₂O₂ (aq) in formic acid, and H₂O₂ in acetic acid.
 32. The methodaccording to claim 31, wherein the oxidizing agent is PAA in AcOH. 33.The method according to claim 16, wherein R₁ is CHF₂.
 34. The methodaccording to claim 16, wherein each Q and each Q_(x) are chloro.